The present invention is directed to mixed salts of essential or semi-essential amino acids and nitrogen-free analogues thereof, and to the use of these novel salts in the treatment of renal and hepatic disorders. More particularly, the invention is directed to the novel compounds per se, compositions containing mixtures of the novel compounds, and methods of treatment using the compounds.
The essential amino acids in man are L-isoleucine, L-leucine, L-valine, L-methionine, L-phenylalanine, L-histidine, L-lysine, L-tryptophan and L-threonine. The semi-essential amino acids for man include L-tyrosine, L-cystine, and L-cysteine, which are believed to be required for optimal growth in infants. Arginine is essential in children who have defects of one of the enzymes of the urea cycle, but is not generally considered essential or semi-essential in normal man, although it may have nutritional value. Ornithine is also not generally considered essential or semi-essential in man, but will substitute for arginine. Nevertheless, for ease of reference in the present disclosure arginine and ornithine will be grouped with and referred to as semi-essential amino acids, unless otherwise indicated.
Renal disorders (such as uremia), hepatic diseases (such as hyperammonemia and portal-systemic encephalopathy), and other protein or nitrogen wasting diseases of man result in severe deficiencies of essential and/or semi-essential amino acids which are needed for building protein in the body. Thus, individuals suffering from renal and hepatic disorders must either be restricted in their ingestion of dietary protein due to the inability of the kidneys to excrete nitrogenous wastes, or they are intolerant of dietary protein due to the vomiting, agitation, lethargy and impaired mental and physical processes which occur following protein ingestion.
Prior art treatment of these protein or nitrogen wasting disorders has included the administration of certain essential amino acids to correct the protein deficiency, such as disclosed in U.S. Pat. No. 2,457,820 to Howe et al. Similarly, Bergstrom et al. in U.S. Pat. No. 3,764,703 disclose the use of a mixture of eight essential amino acids optionally combined with either or both L-arginine and L-histidine, which the patent terms "semi-essential" amino acids, for the treatment of uremic conditions caused by renal insufficiency.
More recently, the treatment of these disorders has been improved by the use of mixtures of nitrogen-free analogues of the essential amino acids, namely alpha-keto and alpha-hydroxy analogues of most of the essential amino acids, together with the essential amino acids per se whose analogues are not available or effective. Examples of such mixtures and treatments are described and claimed in my U.S. Pat. Nos. 4,100,160; 4,100,161 and 4,100,293, issued July 11, 1978. Another treatment of these disorders is disclosed in my U.S. Pat. No. 4,228,099, issued Oct. 14, 1980 entitled "Ornithine And Arginine Salts Of Branched Chain Keto Acids And Uses In Treatment Of Hepatic And Renal Disorders".
A significant obstacle to the use of essential amino acids per se or mixtures of nitrogen-free analogues of essential amino acids in the treatment of these nitrogen or protein wasting disorders is the unpleasant taste of these compounds. Thus, almost all of the essential amino acids per se and all of the keto analogues (as the free acids) are offensive and unpalatable. The calcium and sodium salts of the analogues are not quite as unpleasant as the essential amino acids per se, but can hardly be described as palatable, and therefore present a limitation on the oral use of these compounds for therapeutic purposes. The only oral product presently marketed in this country and containing exclusively essential amino acids is a product marketed by McGaw Laboratories under the trademark "AMINAID", which has a most unpleasant taste. The unpleasant taste can be masked by coating or tableting of the essential amino acids or analogues thereof, but this still leads to complaints of a bad aftertaste.
Another significant obstacle to the use of essential amino acids per se is their limited solubility in water such that they cannot generally be administered parenterally in a concentrated solution. For example, the only commercial product presently on the U.S. market containing solely essential amino acids for injection is a product marketed by McGaw Laboratories under the trademark "NEPHRAMINE". This 5.1 percent aqueous solution of eight essential amino acids (excluding histidine) is very near the limit of solubility at 0.degree. C. The volume of water which must be administered limits the use of this product, especially in severe renal failure.
Although lysine and threonine are very soluble as such, tyrosine and cystine are very insoluble per se. For this reason, the inclusion of tyrosine or cystine in solutions for parenteral administration to infants has been impossible. Cysteine is quite soluble but becomes spontaneously oxidized to its dimer (cystine) in neutral or alkaline solution or on exposure to air. The remaining essential and semi-essential amino acids have variably low solubility.
The acid salts of neutral amino acids, such as the hydrochloride salts, are very soluble. However, the hydrochloride salts are also quite acidic in solution, and since they do not exist above about pH 2, they are never used. The basic amino acids, on the other hand, are often used as the hydrochlorides, because they are less acidic and exist at physiological pH.
The alpha-keto acid analogues and alpha-hydroxy acid analogues are mostly water-miscible liquids, with the exception of the analogues of tryptophan, phenylalanine and tyrosine, which are solids with limited water solubility. The sodium salts of all of the analogues are soluble, but the use of sodium salts is often precluded by the sodium load entailed, which may be detrimental in patients with liver disease or kidney disease in particular. The calcium salts of the analogues are rather insoluble.
A variety of rather cumbersome techniques has been devised or proposed to circumvent these solubility problems. For example, linking tyrosine to another amino acid such as alanine in a peptide bond does solve the solubility problem, but is a very expensive way to go. The keto or hydroxy analogues of tyrosine would presumably be effective, and are somewhat soluble, but they are also very expensive to produce.